Hepatic steatosis provides the terroir that promotes the development of cardiovascular risk factors and disease
Authors: Ian A. Rowe, Alina M. Allen
Journal: Hepatology (2023)

NAFLD is a part of wider dysmetabolism and is associated with other features of the metabolic syndrome. The presence of obesity, insulin resistance, and type 2 diabetes mellitus are often accompanied by dyslipidemia and hypertension in persons with NAFLD. And, while NAFLD is common, complications of liver disease are much less frequent.1 For the clinician coordinating care for a person with NAFLD the issues relating to the metabolic comorbidities are of paramount importance. Assessing the future risks of the commonest cases of morbidity and mortality, namely cardiovascular disease (CVD) and extrahepatic malignancy, are key objectives to allow timely and targeted screening and primary prevention strategies. There has been a great deal of focus on the association between NAFLD and CVD risk over the course of the last decade. The published literature is conflicting with studies and meta-analyses describing independent associations between NAFLD and CVD2 whereas others have not identified such associations.3 Confirmation of an association between NAFLD and incident CVD would be an important contribution to the field. However, the clinical relevance of such an observation will only have substantial value if either a diagnosis of NAFLD adds meaningfully to cardiovascular risk prediction or a therapy developed for NAFLD gains an indication in the primary prevention of CVD. In this issue of HEPATOLOGY, Ahmed et al4 report the findings of a detailed evaluation of incident CVD and CVD-related mortality, together with incident extrahepatic malignancy in 3 well phenotyped cohorts. These cohorts were initially developed for the purpose of cardiovascular risk prediction and had data on all conventional CVD risk factors along with liver fat measured by CT. The presence of such detailed data, available at baseline and in some cases longitudinally, provides a rich resource to answer questions regarding the association between CVD and NAFLD. In short, the authors identify associations between measures of liver fat and incident CVD in univariable analyses, but these associations are not confirmed in multivariable analyses using data at baseline or in time-dependent models. Taking this report alone, it suggests that there is no increased risk of CVD in persons with NAFLD above that conferred by other metabolic comorbidities. The wider context of the field is important, however. The most recent (of several) systematic reviews and meta-analyses of the topic describe incident CVD events and mortality in over 5 million persons with and without NAFLD.2 Considering only studies described to have a complete adjustment for conventional cardiovascular risk factors there remains an independent association between NAFLD and incident CVD and CVD-related mortality. The HR for the association between NAFLD and fatal CVD events in the pooled analyses was 1.42 and for nonfatal events, it was 1.31. Inevitably, not all described risk factors have been considered in the studies considered in the systematic review, nor indeed in the report from Ahmed and colleagues. For instance, waist circumference is known to be associated with both CVD and NAFLD. This is infrequently measured (and is challenging to do so in a reproducible way) but the lack of availability of additional confounders is a continuing limitation of the current literature. The contribution of unmeasured confounding to the estimates of increased CVD risks with NAFLD remains a critical question. Current epidemiological methods allow an estimation of the effect of the size of unmeasured confounding that would need to be present to negate the observed observation.5 The E value provides this estimate and, for the example above describing the association between NAFLD and nonfatal CVD events, the E value is 1.95. The E value for the upper limit of the CI is 1.37. Practically this means that unmeasured confounding could explain the observed association if the HR was at least as large as 1.95 for both NAFLD and nonfatal cardiovascular events. To further judge the relevance of this finding, one can use the bias factor approach comparing known confounders.6 In this example, we can use type 2 diabetes because this is associated with both NAFLD (HR=2 after adjustment for body mass index)7 and incident CVD events (HR=1.5).8 Taking these data from existing large studies, the bias factor is 1.4, which is greater than the observed association between NAFLD and nonfatal CVD events from the pooled meta-analysis. Overall, this suggests that residual unmeasured confounding could still be a major player in the described observation between NAFLD and CVD risk. Regardless of this discussion of the association between NAFLD and CVD, the question remains, what is the relevance of this to a patient with or at risk of NAFLD? CARDIOVASCULAR RISK PREDICTION The purpose of prognostic factor research is to aid information giving and therapeutic decision-making for persons with a given disease, in this case, NAFLD. Understanding that CVD events are the commonest cause of mortality in persons with NAFLD provides opportunities for education and the potential for therapeutic intervention. The paradigm in cardiovascular risk prediction is set on the identification of key disease drivers, such as diabetes and hypertension, and using lipid-lowering therapy according to CVD risk. The treatment threshold has been set according to health economic analyses considering the relevant trade-offs of treatment. The major missing piece in the jigsaw where persons with NAFLD are concerned are studies that specifically address the added value of the presence of NAFLD in CVD risk prediction. Where prognosis and risk prediction differed according to the diagnosis of NAFLD, this would provide impetus to increase diagnosis of NAFLD in primary care (to aid CVD risk prediction rather than because of the liver disease itself) and treatment to reduce that risk. There are studies that inform this question of whether NAFLD is likely to be meaningfully additive in CVD risk prediction. Perhaps most importantly, large-scale studies that incorporate measures of visceral adiposity such as waist circumference and waist-to-hip ratio do show associations with CVD but these do not add to the accuracy of CVD risk prediction.9 Taken together with the findings from the meta-analysis of the association of NAFLD with CVD events, the probability of continued unmeasured confounding, and the report from Ahmed and colleagues, it seems unlikely that NAFLD will emerge as an important predictor in the calculation of CVD risk. At present, while a diagnosis of NAFLD should prompt a CVD risk assessment, this should be managed in the same way as for a person without NAFLD. Nevertheless, the impact of NAFLD on these outcomes is not null. As shown in previous population-based studies, the presence of NAFLD increases the risk of incident comorbidities such as diabetes and hypertension by more than 2-fold.10 As a precursor to diseases that are known to increase the risk of CVD, NAFLD remains important to recognize and treat. Importantly, subsequent development of metabolic comorbidities should be taken into consideration as time-dependent covariates in all time-to-event analyses of NAFLD outcomes, which otherwise confound the impact of NAFLD alone, as seen in the case of mortality estimation in the paper by Ahmed and colleagues. Treatment of patients with NAFLD The purpose of treating a patient with liver disease is usually to prevent the progression of that disease and downstream complications. It is interesting that in persons with NAFLD, even those with relatively advanced disease, most often experience and ultimately die from complications of their wider dysmetabolic phenotype. This presents a challenge to clinicians managing persons with liver disease, to drug developers, as well as to regulators and payers. Given the direction of current drug development in NASH, the favorable impacts of treatment on the associated dysmetabolism suggests that there may be significant gains for the person with NASH beyond their liver disease. These additional treatment benefits are perhaps best exemplified by the parallel development of semaglutide in diabetes, obesity, and NASH. There is established CVD risk reduction with semaglutide in persons with diabetes11 and trials are underway to establish its benefit in persons with obesity (https://www.clinicaltrials.gov, NCT03574597). It is possible, given the low rates of clinical liver events in prior phase 3 trials in NASH, that treatment with semaglutide will prevent more CVD events in the ongoing phase 3 trial (https://www.clinicaltrials.gov, NCT04822181) than liver events. While this is an important secondary endpoint in the trial, this is of critical importance to the person with NASH regardless of the impact of treatment on their liver disease. Developing structures where drugs with pleiotropic metabolic effects can be tested is a priority. The article by Ahmed and colleagues is an excellent contribution to understanding the association between NAFLD and CVD events and another opportunity to describe the relationships between NAFLD and the wider dysmetabolic phenotype. Hepatic steatosis may not be an independent predictor of CVD events but rather contributes to the terroir for the further development of diabetes and hypertension that drive increased CVD risk in persons with NAFLD. The research agenda now needs to change focus away from descriptive epidemiology toward questions with direct relevance to patients, including how a diagnosis of NAFLD impacts CVD risk prediction and treatments in development for NAFLD are best implemented.